The present invention relates to epothilone analogs having side chain modifications and to methods for producing such compounds using solid phase and solution phase chemistries.
The epothilones (1-5, FIG. 1) are natural substances which exhibit cytotoxicity against taxol-resistant tumor cells by promoting the polymerization of xcex1- and xcex2-tubulin sub-units and stabilizing the resulting microtubule assemblies. Epothilones displace Taxol(trademark) from its microtubul binding site and are reported to be about 2000-5000 times more potent than Taxol with respect to the stabilization of microtubules.
What is needed are analogs of epothilone A and B and libraries of analogs of epothilone A and B that exhibit superior pharmacological properties in the area of microtubule stabilizing agents.
Furthermore, what is needed are methods for producing synthetic epothilone A, epothilone B, analogs of epothilone A and B, and libraries of epothilone analogs, including epothilone analogs possessing both optimum levels of microtubule stabilizing effects and cytotoxicity.
One aspect of the invention is directed to an epothilone analog represented by the following structure: 
In the above structure, R2 is absent or oxygen; xe2x80x9caxe2x80x9d can be either a single or double bond; xe2x80x9cbxe2x80x9d can be either absent or a single bond; and xe2x80x9ccxe2x80x9d can be either absent or a single bond. However, the following provisos apply: if R2 is oxygen, then xe2x80x9cbxe2x80x9d and xe2x80x9ccxe2x80x9d are both a single bonds and xe2x80x9caxe2x80x9d is a single bond; if R2 is absent, then xe2x80x9cbxe2x80x9d and xe2x80x9ccxe2x80x9d are absent and xe2x80x9caxe2x80x9d is a double bond; and if xe2x80x9caxe2x80x9d is a double bond, then R2, xe2x80x9cbxe2x80x9d, and xe2x80x9ccxe2x80x9d are absent. R3 is a radical selected from the group consisting of hydrogen, methyl, xe2x80x94CHO, xe2x80x94COOH, xe2x80x94CO2Me, xe2x80x94CO2(tert-butyl), xe2x80x94CO2(iso-propyl), xe2x80x94CO2(phenyl), xe2x80x94CO2(benzyl), xe2x80x94CONH(furfuryl), xe2x80x94CO2(N-benzo-(2R,3S)-3-phenylisoserine), xe2x80x94CONH(methyl)2, xe2x80x94CONH(ethyl)2, xe2x80x94CONH(benzyl), xe2x80x94CHxe2x95x90CH2, xe2x80x94Cxe2x89xa1CH, and xe2x80x94CH2R11, wherein R11 is a radical selected from the group consisting of xe2x80x94OH, xe2x80x94O-Trityl, xe2x80x94Oxe2x80x94(C1-C6 alkyl), xe2x80x94(C1-C6 alkyl), xe2x80x94O-benzyl, xe2x80x94O-allyl, xe2x80x94Oxe2x80x94COCH3, xe2x80x94Oxe2x80x94COCH2Cl, xe2x80x94Oxe2x80x94COCH2CH3, xe2x80x94Oxe2x80x94COCF3, xe2x80x94Oxe2x80x94COCH(CH3)2, xe2x80x94Oxe2x80x94COC(CH3)3, xe2x80x94Oxe2x80x94CO(cyclopropane), xe2x80x94OCO(cyclohexane), xe2x80x94Oxe2x80x94COCHxe2x95x90CH2, xe2x80x940xe2x80x94COxe2x80x94Phenyl, xe2x80x94O-(2-furoyl), xe2x80x94O-(N-benzo-(2R,3S)-3-phenylisoserine), xe2x80x94O-cinnamoyl, xe2x80x94O-(acetyl-phenyl), xe2x80x94O-(2-thiophenesulfonyl), xe2x80x94Sxe2x80x94(C1-C6 alkyl), xe2x80x94SH, xe2x80x94S-Phenyl, xe2x80x94S-Benzyl, xe2x80x94S-furfuryl, xe2x80x94NH2, xe2x80x94N3, xe2x80x94NHCOCH3, xe2x80x94NHCOCH2Cl, xe2x80x94NHCOCH2CH3, xe2x80x94NHCOCF3, xe2x80x94NHCOCH(CH3)2, xe2x80x94NHCOC(CH3)3, xe2x80x94NHCO(cyclopropane), xe2x80x94NHCO(cyclohexane), xe2x80x94NHCOCHxe2x95x90CH2, xe2x80x94NHCO-Phenyl, xe2x80x94NH(2-furoyl), xe2x80x94NH-(N-benzo-(2R,3S)-3-phenylisoserine), xe2x80x94NH-(cinnamoyl), xe2x80x94NH-(acetyl-phenyl), xe2x80x94NH-(2-thiophenesulfonyl), xe2x80x94F, xe2x80x94Cl, I, and xe2x80x94CH2CO2H. R4 and R5 are each independently selected from hydrogen, methyl or a protecting group. R1 is a radical selected from the following structures: 
In a preferred embodiment, R3 is hydrogen or xe2x80x94CH2R11, R11 is a radical selected from the group consisting of xe2x80x94OH and xe2x80x94F, and R1 is a radical selected from the following structures: 
Another aspect of the invention is directed to a process for synthesizing an epothlone analog, or a salt thereof The process includes a coupling step wherein an epothilone intermediate and an aromatic stannane are coupled by means of a Stille coupling reaction for producing the epothilone analog. The epothilone is represented by the following structure: 
The epothilone intermediate is represented by the following structure: 
In the above structures, R1 and R4 are each independently selected from hydrogen, methyl or a protecting group; R5 is xe2x80x94CH2Rx wherein Rx is a radical selected from the group consisting of xe2x80x94OH, xe2x80x94O-Trityl, xe2x80x94Oxe2x80x94(C1-C6 alkyl), xe2x80x94(C1-C6 alkyl), xe2x80x94O-benzyl, xe2x80x94O-allyl, xe2x80x94Oxe2x80x94COCH3, xe2x80x94Oxe2x80x94COCH2Cl, xe2x80x94Oxe2x80x94COCH2CH3, xe2x80x94Oxe2x80x94COCF3, xe2x80x94Oxe2x80x94COCH(CH3)2, xe2x80x94Oxe2x80x94COC(CH3)3, xe2x80x94Oxe2x80x94CO(cyclopropane), xe2x80x94OCO(cyclohexane), xe2x80x94Oxe2x80x94COCHxe2x95x90CH2, xe2x80x94Oxe2x80x94CO-Phenyl, xe2x80x94O-(2-furoyl), xe2x80x94O-(N-benzo-(2R,3S)-3-phenylisoserine), xe2x80x94O-cinnamoyl, xe2x80x94O-(acetyl-phenyl), xe2x80x94O-(2-thiophenesulfonyl), xe2x80x94Sxe2x80x94(C1-C6 alkyl), xe2x80x94SH, xe2x80x94S-Phenyl, xe2x80x94S-Benzyl, xe2x80x94S-furfuryl, xe2x80x94NH2, xe2x80x94N3, xe2x80x94NHCOCH3, xe2x80x94NHCOCH2Cl, xe2x80x94NHCOCH2CH3, xe2x80x94NHCOCF3, xe2x80x94NHCOCH(CH3)2, xe2x80x94NHCOC(CH3)3, xe2x80x94NHCO(cyclopropane), xe2x80x94NHCO(cyclohexane), xe2x80x94NHCOCHxe2x95x90CH2, xe2x80x94NHCO-Phenyl, xe2x80x94NH(2-furoyl), xe2x80x94NH-(N-benzo-(2R,3S)-3-phenylisoserine), xe2x80x94NH-(cinnamoyl), xe2x80x94NH-(acetyl-phenyl), xe2x80x94NH-(2-thiophenesulfonyl), xe2x80x94F, xe2x80x94Cl, xe2x80x94I, and xe2x80x94CH2CO2H and methyl; and the aromatic stannane is a compound represented as (Ry)3Snxe2x80x94R10 wherein Ry is either n-butyl or methyl; R10 is a radical selected from a group consisting of one of the following structures: 
and (in a broader aspect of the invention) 
wherein Rx is acyl, especially lower alkanoyl, such as acetyl.